title: Effective progression of nuclear magnetic resonance-detected fragment hits.
abstract: Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade as an alternate lead generation tool to HTS approaches. Several compounds have now progressed into the clinic which originated from a fragment-based approach, demonstrating the utility of this emerging field. While fragment hit identification has become much more routine and may involve different screening approaches, the efficient progression of fragment hits into quality lead series may still present a major bottleneck for the broadly successful application of FBDD. In our laboratory, we have extensive experience in fragment-based NMR screening (SbN) and the subsequent iterative progression of fragment hits using structure-assisted chemistry. To maximize impact, we have applied this approach strategically to early- and high-priority targets, and those struggling for leads. Its application has yielded a clinical candidate for BACE1 and lead series in about one third of the SbN/FBDD projects. In this chapter, we will give an overview of our strategy and focus our discussion on NMR-based FBDD approaches.
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Hugh L
authors.initials: HL
authors.lastname: Eaton
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055592:Biophysical Phenomena; D020134:Catalytic Domain / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D006827:Hydantoins / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D011485:Protein Binding; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013890:Thiourea / Q000031:analogs & derivatives
chemical_list: D006827:Hydantoins; D008024:Ligands; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D013890:Thiourea